Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch.
To elucidate the molecular mechanisms whereby expanded polyglutamine stretches elicit a gain of toxic function, we expressed full-length and truncated DRPLA (dentatorubral-pallidoluysian atrophy) cDNAs with or without expanded CAG repeats in COS-7 cells. We found that truncated DRPLA proteins containing an expanded polyglutamine stretch form filamentous peri- and intranuclear aggregates and undergo apoptosis. The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases.
Igarashi
S
S
Department of Neurology, Brain Research Institute, Niigata University, Asahimachi Niigata, Japan.
Koide
R
R
Shimohata
T
T
Yamada
M
M
Hayashi
Y
Y
Takano
H
H
Date
H
H
Oyake
M
M
Sato
T
T
Sato
A
A
Egawa
S
S
Ikeuchi
T
T
Tanaka
H
H
Nakano
R
R
Tanaka
K
K
Hozumi
I
I
Inuzuka
T
T
Takahashi
H
H
Tsuji
S
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D019556:COS Cells; D002103:Cadaverine / Q000031:analogs & derivatives / Q000494:pharmacology; D003538:Cystamine / Q000494:pharmacology; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics; D011700:Putrescine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D011503:Transglutaminases / Q000037:antagonists & inhibitors*; D018911:Trinucleotide Repeats
D017931:DNA Primers; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C095278:atrophin-1; D011503:Transglutaminases; C008542:monodansylcadaverine; D002103:Cadaverine; D003538:Cystamine; D011700:Putrescine